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TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines
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Journal Article
TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines
2008
Overview
DNA vaccines induce adaptive immune responses mainly via induction of type-I interferon. This paper shows that this occurs by a mechanism that is independent of the activation of nucleic acid binding Toll-like receptors. B and CD4
+
T cell responses require activation of the TBK pathway in hematopoietic cells, whereas TBK1 in non-hematopoietic cells is critical for the activation of CD8
+
T cells.
Successful vaccines contain not only protective antigen(s) but also an adjuvant component that triggers innate immune activation and is necessary for their optimal immunogenicity
1
,
2
. In the case of DNA vaccines
3
, this consists of plasmid DNA; however, the adjuvant element(s) as well as its intra- and inter-cellular innate immune signalling pathway(s) leading to the encoded antigen-specific T- and B-cell responses remain unclear. Here we demonstrate
in vivo
that TANK-binding kinase 1 (TBK1), a non-canonical IκB kinase, mediates the adjuvant effect of DNA vaccines and is essential for its immunogenicity in mice. Plasmid-DNA-activated, TBK1-dependent signalling and the resultant type-I interferon receptor-mediated signalling was required for induction of antigen-specific B and T cells, which occurred even in the absence of innate immune signalling through a well known CpG DNA sensor—Toll-like receptor 9 (TLR9) or Z-DNA binding protein 1 (ZBP1, also known as DAI, which was recently reported as a potential B-form DNA sensor
4
). Moreover, bone-marrow-transfer experiments revealed that TBK1-mediated signalling in haematopoietic cells was critical for the induction of antigen-specific B and CD4
+
T cells, whereas in non-haematopoietic cells TBK1 was required for CD8
+
T-cell induction. These data suggest that TBK1 is a key signalling molecule for DNA-vaccine-induced immunogenicity, by differentially controlling DNA-activated innate immune signalling through haematopoietic and non-haematopoietic cells.
Publisher
Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
Subject
/ Antigens
/ Biological and medical sciences
/ DNA
/ Fundamental and applied biological sciences. Psychology
/ Genetics of the immune response
/ Humanities and Social Sciences
/ Immunity, Innate - immunology
/ Interferon Type I - immunology
/ Interferon Type I - metabolism
/ Kinases
/ letter
/ Mice
/ Protein-Serine-Threonine Kinases - deficiency
/ Protein-Serine-Threonine Kinases - genetics
/ Protein-Serine-Threonine Kinases - metabolism
/ Receptor, Interferon alpha-beta - deficiency
/ Receptor, Interferon alpha-beta - genetics
/ Receptor, Interferon alpha-beta - metabolism
/ Science
/ Toll-Like Receptor 9 - deficiency
/ Toll-Like Receptor 9 - genetics
/ Toll-Like Receptor 9 - metabolism
/ Vaccines
